1. Field of the Invention
This invention relates to photoactivatable compounds and to methods for using the compounds for diagnosing and treating medical conditions.
2. Prior Art
Photodynamic Therapy (PDT) is used for treating various diseases including cancer, psoriasis, vascular disease, non-cancerous hyperplastic disease such as benign prostatic hyperplasia, macular degeneration, glaucoma, and certain viral infections. PDT requires concentrating a photosensitizer drug in a target tissue then photoactivating the compound with a device which includes a light source providing light at a particular wavelength and power level. The drugs administered for PDT are commonly known as photosensitizers (PS) due to their inherent ability to absorb photons of light and transfer that energy to oxygen which then converts to a cytotoxic or cytostatic species. Table 1 presents a list of classes of photosensitizer compounds commonly employed in PDT, which PS's are referred to hereinafter in the alternative as "ROPPs" (Reactive Oxygen Producing Photosensitizer molecules) and "LEPs" (Light Emitting Photosensitive molecules). While not exhaustive, the list of PDT photosensitizer drugs presented in Table 1 is exemplary of the variety of ROPPs and LEPs currently used in the art.
The photoactivating device employed for PDT usually comprises a monochromatic light source such as a laser, the light output of which may be coupled to an invasive light delivery catheter for conduction and delivery to a remote target tissue. Such interventional light delivery catheters are well known in the art and are described, for example, in U.S. Pat. Nos. 5,169,395; 5,196,005; and 5,231,684. Other devices which are frequently used in conjunction with a light source and light delivery catheter include drug delivery devices and/or a balloon perfusion catheter (U.S. Pat. No. 5,213,576) and/or various medicament-dispensing stents for the slow localized release of the photosensitizer. PDT is presently an approved procedure in Canada, Japan, and The Netherlands for the treatment of various cancers.
In addition to cancer therapy, PDT is being tested for the treatment of psoriasis. Extra-corporal PDT of blood is being evaluated for the prevention of intimal hyperplasia following transplant surgery. PDT is also being evaluated for the treatment of vascular disease; most commonly the prevention of intimal hyperplasia following angioplasty. ROPPs are presently in clinical trials for the treatment of cutaneous cancers such as basal cell carcinoma, basal cell nevus syndrome, squamous cell carcinoma, and AIDS related Kaposi's sarcoma. ROPPs are also being investigated for the treatment of a cancer precursor, Barrett's esophagus. In addition, ROPPs may have utility for treating invasive cancers, cancer precursors, psoriasis, non-cancerous urological disorders, viral inactivation, macular degeneration, glaucoma and various vascular diseases.
TABLE 1 ______________________________________ ROPPs and LEPs ______________________________________ Pyrrole-derived macrocyclic Texaphyrins and derivatives compounds thereof (11) Naturally occurring or synthetic Phenoxazine dyes and derivatives porphyrins and derivatives thereof (12) thereof (1)* Phenothiazines and derivatives Naturally occurring or synthetic thereof (13) chlorins and derivatives thereof (2) Chalcoorganapyrylium dyes and Naturally occurring or synthetic derivatives thereof (14) bacteriochlorins and derivatives Triarylmethanes and derivatives thereof (3) thereof (15) Synthetic isobacteriochlorins and Rhodamines and derivatives derivatives thereof (4) thereof (16) Phthalocyanines and derivatives Fluorescenes and derivatives thereof (5) thereof (17) Naphthalocyanines and derivatives Azaporphyrins and derivatives thereof (6) thereof (18) Porphycenes and derivatives Benzochlorins and derivatives thereof (7) thereof (19) Porphycyanines and derivatives Purpurins and derivatives thereof (8) thereof (20) Pentaphyrin and derivatives Chlorophylls and derivatives thereof (9) thereof (21) Sapphyrins and derivatives Verdins and derivatives thereof (22) thereof (10) ______________________________________ *(m) refers to the compound having molecular structure indicated at (m) i the specification where m is an integer between 1 and 22.
ROPPs and LEPs such as those indicated in Table 1, and as illustrated in FIGS. 1-23, have been shown to selectively accumulate, both in vitro and in vivo, in catheter induced atheromatous plaques in rabbit and swine models as evidenced by laser induced fluorescence and chemical extraction (H L Narciso, et al, Retention of tin ethyl etiopurpurin (SnET2) by atheromatous plaques: Studies in vitro & in vivo rabbits, Proceedings of SPIE: Diagnostic and Therapeutic Cardiovascular Interventions IV, 1994, 2130:30-41). In vitro studies utilizing human cadaver aortas demonstrate the passive accumulation of photosensitizers such as ROPPs and LEPs into naturally occurring atheromatous plaques. Certain ROPPs and LEPs have the ability to penetrate the nuclear membrane within a cell and to intercalate into the nuclear DNA, particularly ROPPs bearing a positive charge (cationic).
Psoralen-type compounds have also been investigated for their ability to prevent intimal hyperplasia. Psoralens and other furocoumarins (furane fused to coumarin and derivatives thereof) are also photosensitive compounds which have been used in the treatment of psoriasis for over 40 years. Such psoralen-based phototherapy is alternatively referred to herein as PUVA; Psoralen activated with UltraViolet A light. An exemplary list of some furocourmarin compounds is presented in Table 2. Systemically administered psoralen-type compounds penetrate the nuclear membrane of cells and may intercalate with the nuclear DNA in target tissue cells. Following intercalation with the target tissue's nuclear DNA, the psoralen compound is photoactivated with ultraviolet light or short wavelength visible light (see, for example, F P Gasparro, et al, The excitation of 8-Methoxypsoralen with visible light: Reversed phase HPLC quantitation of monoadducts and cross-links, Photochem. Photobiol., 1993, 57(6):1007-1010.), which UV light is preferably delivered only to the target tissue by a light delivery catheter or similar delivery device, to cause DNA crosslinking and ultimately a mutagenic effect in the cells comprising the target tissue. (K L March, et al, 8-Methoxypsoralen and longwave ultraviolet irradiation are a novel antiproliferative combination for vascular smooth muscle, Circulation, 1993, 87:184-91; B E Sumpio, et al, Control of smooth muscle cell proliferation by psoralen photochemotherapy, J Vasc. Surg, 1993, 17:1010-1018; K W Gregory, et al, Photochemotherapy of intimal hyperplasia using psoralen activated by ultraviolet light in a porcine model, Lasers in Surg. Med, 1994, (Suppl 6):12 Abstract).
Furocoumarins are photochemical agents showing potential for both diagnostic and therapeutic applications in medicine. The DNA cross-linking by furocoumarins such as described above proceeds by a two step process. Following injection of the fuorocoumarin into the body of an animal, the (planar) furocoumarin molecule first intercalates within the double helix of intracellular DNA or RNA Following intercalation, the covalent addition of the furocoumarin to the polynucleic acid is achieved through the addition of light energy within the absorption band of the specific furocoumarin. Either furocoumarin -RNA or -DNA monoadducts or cross-links may be created upon illumination of the intercalated species. By forming covalent cross-links with base-pair structures, furocoumarins can alter the metabolic activity of a cell and induce cytostasis (G D Cimino, H B Gamper, S T Isaacs, J E Hearst, Psoralens as photoactive probes of nucleic acid structures and function: Organic chemistry, and biochemistry Ann. Rev. Biochem., 1985, 54:1154-93).
TABLE 2 ______________________________________ Furocoumarins.dagger-dbl. ______________________________________ Compounds containing Furocoumarin sub-components (23)* Psoralens and derivatives thereof (24) Isopsoralens (angelicins) and derivatives thereof (25) Pseudopsoralens and derivatives thereof (26) Pseudoisopsoralens and derivatives thereof (27) Allopsoralens and derivatives thereof (28) Pseudoallopsoralens and derivatives thereof (29) ______________________________________ *(m) refers to the compound having the structure indicated at FIG. m in the appended figures where m is an integer 23 .ltoreq. m .ltoreq. 29. .dagger-dbl.The furocoumarins may be either naturally occurring or synthetic.
Coronary artery disease is thought to be initiated by a disruption of fatty streaks which form early in life on the vessel wall which disruption, in turn, promotes thrombus formation. Over time the thrombus becomes organized and provides structure for the accumulation of fatty lipids, foam cells, cholesterol, calcium, fibrin, and collagen. A fibrous cap forms over this collection of lipid-rich material. Periodically this fibrous cap ruptures; releasing some of the lipid-rich material and exposing the remaining plaque materials to the circulating blood. Growth factors within the blood initiate the migration of smooth muscle cells (SMCs), from the media to the intima where proliferation of the SMCs begins. The ulcerated plaque induces the deposition of platelets and thrombus formation in a "response to injury" mode. This cycle recurs until eventually the plaque ruptures, the distal coronary artery is occluded by an thrombus and a heart attack occurs (V. Fuster, et al, Clinical-Pathological Correlations of Coronary Disease Progression and Regression, Supplement to Circulation, Vol. 86, No. 6, 1992:III-1-III-11 and J J Badimon, Coronary Atherosclerosis, A Multifactorial Disease, Supplement to Circulation, Vol. 87, No. 3, 1993:II-3-II-16).
Restenosis occurs when coronary disease is treated with an interventional therapy such as Percutaneous Transluminal Coronary Angioplasty, PTCA, or atherectomy, or laser angioplasty, or stenting, or a myriad of newer technologies. Restenosis refers to the over-aggressive autogenous repair of an injury to a blood vessel by the body. Intimal hyperplasia or the hyperproliferation of medial (and possibly adventitial) smooth muscle cells (SMCs,) is a major contributing factor to restenosis. Hyperproliferating SMCs form a neo-intima which can reduce the bore of the arterial lumen and thus the capacity of the artery to deliver oxygen rich blood. This reduction in cross-sectional luminal area can be more severe than the original constricted area which was treated. The foregoing problems are representative of some medical conditions which the compounds of the present invention may have particular application.
DNA cross-linking by furocoumarins results in the reduction of smooth muscle cell (SMC) proliferation and, since their DNA cross-linking activity is cytostatic, furocoumarins may have certain advantages over cytotoxic photosensitizers (ROPPs and LEPs) in the prevention of intimal hyperplasia as described by March, et al, U.S. Pat. No. 5,116,864 and Deckelbaum, et al, U.S. Pat. No. 5,354,774 the teachings of which patents are incorporated herein by reference thereto. The cytotoxicity of ROPPs and LEPs currently used in PDT results in the extravasation of intracellular organelles, cytoplasm, and cytokines which, in turn, elicits an inflammatory response. The inflammatory response elicited by extravasation of cellular contents is hypothesized as a key contributing factor to restenosis. The disadvantage of employing psoralens to prevent restenosis (when compared to photosensitizers such as ROPPs and LEPs) is that psoralens do not exhibit a selective affinity for atheromatous plaques over normal intimal tissue.